Bio 113/244 Fundamentals of Molecular Evolution
Professor:
Dmitri Petrov (dpetrov@stanford.edu, 650 736 1169).
Office: Herrin Labs, room 352B
Lectures:
TTh 2:15 – 3:30 PM, Bldg 370, Room 370
Discussion sections: Once a week. Mandatory.
Office Hours: by appt
Web page: Find Biosci113/244 through http://coursework.stanford.edu
The page has problem sets, past exams, list of terms, useful derivations, and
copies of lectures from the past time this class was taught. It will also contain
lectures scribed by the students in this class.
Prerequisites: The BioCore OR graduate standing OR permission of the
instructor.
Teaching Asistants: Diamantis Sellis <dsellis@stanford.edu> and Sandeep
Venkataram <svenkat1@stanford.edu>
Any questions: E-mail them to bio113.2011@gmail.com.
Scheduling sections: Add you preference to the doodle poll. You can find the
addresses on the coursework site. Undergraduates should use the bio113 poll
and the graduate students the 244 one. The location will be announced once we
know the times.
Scribing: All students are required to help with creating the record of the class
lectures that will posted on the web to help everyone to study. The details are
forthcoming.
Project: Students are expected to organize themselves into groups of 3-6 people
with a good mix of computational/statistical students with the students focusing
primarily on biology. The group is responsible for carrying out an independent
project that is supposed to do something new and interesting. What that means
will become clear in discussion. The project proposals are due on April 19 and
the proposals will be presented as 10 min powerpoint presentations (with pizza)
on the final day of the class.
Exams: All exams are take home. There is one midterm (take home on Thursday,
April 21, back by lecture time on Tuesday, April 26) and the final exam (take
home on Tuesday, May 31, back by 10AM on Tuesday, June 7). You are free to
use lecture notes, any books or web materials you choose. Do not consult with
one another. Late exams will not be accepted.
Grading:
Participation in sections
10%
Final Project
10%
Midterm
30%
Final exam
50%
Texts:

Fundamentals of Molecular Evolution by Dan Graur, Wen-Hsiung Li (FME)
Sinauer Assoc; ISBN: 0878932666; 2nd edition (January 2000)

Population Genetics: A Concise Guide by John H. Gillespie (PG)
Publisher: Johns Hopkins Univ Pr; ISBN: 0801880092; 2nd edition (July 2004)
Syllabus
Tue, Mar 29
Introduction. The very brief history of evolutionary biology. Darwin
and Wallace. The neo-Darwinian synthesis. Fisher, Dobzhansky, Mayr,
Simpson. What is molecular evolution? What do you need to know to
succeed in this class? Logistics.
Thu, Mar 31
Molecular evolutionary data. Polymorphism, divergence, and mutation.
Mutation vs substitution. Importance of understanding population
processes in order to understand the evolutionary process. Inference of
the individual evolutionary events from the final outcomes. DNA
sequence as repeated trials. The concept of a “rate” of molecular
evolution. Homology assignment and the problem of multiple hits.
Jukes-Cantor (JC) correction.
reading: FME 67-79
Tue, Apr 5
JC correction revisited. Saturation. Mutation. Types and chemical basis
of mutation. Transitions and transversions. Deletions and insertions.
Gene duplications. Kimura’s 2-parameter correction. Analysis of
substitutions in protein sequences. Replacement and synonymous
substitutions. Data. Observation that the rate of replacement
substitutions in general is lower than that of synonymous substitutions.
Why?
reading: FME 5-38, 79-85,
Thu, Apr 7
Non-randomness imposed by selection and genetic code structure. Less
variation in the rate of synonymous than non-synonymous evolution
among different proteins. Multiple hit correction in protein sequences.
The problem of choosing among different paths. The idea of deleterious,
advantageous, and neutral mutations. The observation of the molecular
clock. The first appearance of the neutral theory.
reading: FME 99-117
Tue, Apr 12
The process of evolution -- population genetics. Allele (gene) and
genotype frequencies. Evolution as “mutation + change in gene
frequency”. Random mating and Hardy-Weinberg (HW) equilibrium.
Heterozygosity. Relationship between gene frequency and
heterozygosity. Extension of the concept to multiple alleles, non-HW
equilibrium and even to non-diploid organisms.
reading: PG 1-18
Thu, Apr 14
Random genetic drift (RGD) and binomial sampling. Probability of
fixation of neutral alleles. Rate of neutral substitution. Loss of
heterozygosity through RGD. Infinite allele model. Derivation of the
rate of loss of heterozygosity. Time scales of drift and mutation. Theta
as the measure comparing rates of mutation and the speed of mutation.
Theta and the effective population size.
reading: PG 19-40; 47-49
Tue, Apr 19
DNA sequence data. Infinite sites model. Pairwise divergence as the
measurement of theta. Coalescence. Measuring theta through the
number of segregating sites.
Natural selection. Basic viability selection model and heterozygous
effect.
reading: PG 40-47, 59-70
Thu, Apr 21
Continuing thinking about natural selection. Importance of
heterozygosity to selection. Strong selection and mutation-selection
balance. "Reasonable" values of selection coefficients and heterozygous
effects. Genetic load and the law of the “conservation of misery”
MIDTERM IS HANDED OUT.
reading: PG 59-71
Tue, Apr 26
EXAM IS DUE AT THE BEGINNING OF THE LECTURE AT 2:15.
LATE EXAMS WILL NOT BE ACCEPTED.
Interaction between drift and natural selection. Diffusion
approximation. Probability of fixation of mutations with weak selective
effects. Rare alleles -- interaction between drift and selection.
Asymmetry between purifying and positive selection.
reading: PG 91-98; Appendix B
Thu, Apr 28
Neutral theory. Constraint and neutral mutation rate. Molecular clock.
Reading of the Kimura/Ohta paper. Puzzle over the constancy of the
rate in absolute time, rather in the number of generations. Nearlyneutral theory and the effectively neutral mutation rate.
reading: FME 139-154, PG 32-35
Kimura & Ohta, Protein polymorphism as a phase of molecular
evolution. Nature, 1971, v. 229, pp. 467-69
Tue, May 3
Testing neutral theory. Review of basic statistics summarizing
polymorphism. Tajima’s D tests. Connecting polymorphism and
divergence. Macdonald-Kreitman test. Examples from literature.
reading: FME 63-64
McDonald & Kreitman, 1991. Adaptive evolution at the Adh locus in
Drosophila. Nature, v. 351, 652-654.
Thu, May 5
Positive selection and adaptive evolution. Ka/Ks measurements.
Evolution of lysozyme in langur monkeys. Contribution of neutral,
slightly deleterious and advantageous mutations to evolution.
reading: FME 119-124
Messier & Stewart. 1997. Episodic adaptive evolution of primate
lysozymes. Nature, v. 385, 151-154.
Smith & Eyre-Walker. 2002. Adaptive protein evolution in Drosophila.
Nature, v. 415, 1022-1024.
Eyre-Walker, A. The genomic rate of adaptive evolution. Trends Ecol
Evol 21, 569-75 (2006).
Tue, May 10
Joint effects of genetic linkage and selection. Muller’s ratchet, selective
sweeps, and background selection. Testing predictions of background
selection and selective sweeps.
Begun & Aquadro. 1992. Levels of naturally occurring polymorphism
correlate with recombination rates in D. melanogaster. Nature, v. 356,
519-520.
Thu, May 12
Genetic draft. Evidence from Drosophila.
reading: PG 105-117.
Macpherson, Sella, Davis, & Petrov. Genetics (submitted)
Tue, May 17
Codon bias and selection at synonymous sites. Evolution through
mutational bias. Using variation in recombination rate across the
genome as a proxy for the variation in the effective population size.
reading: FME 132-139
Thu, May 19
Genome evolution. GC content evolution. Biased gene conversion.
reading: FME 367-390
Tue, May 24
Genome evolution. Evolution by gene duplication. Paralogy and
orthology. Dating gene duplications. Probability of nonfunctionalization
and subfunctionalization.
reading: FME 250-255, 271-283
Thu, May 25
Force et al. 1999. Preservation of duplicate genes by complementary,
degenerative mutations. Genetics, v. 151, 1531-1545.
Genome evolution. Evolution of genome size. Evolution by transposition.
reading:
Petrov, D. A. Evolution of genome size: new approaches to an old
problem. Trends Genet 17, 23-8. (2001).
Tue, May 31
Final review. The Final Exam is given out.
Tue, June 7
The Final exam is due in Herrin 352B by 10AM. Late exams will not
be accepted.